1-(paraoxybenzyl)-indanes

ABSTRACT

The present invention is directed to 1-(4-substituted benzyl)indans and simple analogs thereof; they have been found to inhibit the metabolic function of reproductive organs when administered to female, warm-blooded animals in very small doses.

United States Patent Lynch et a]. [4 1 Aug. 1, 1972 [54]l-(PARAOXYBENZYL)-INDANES [56] References Cited [72] Inventors: Don MurlLynch, Waukegan; John Wayne Cole, Deerfield, both of 111. UNITED STATESPATENTS [73] Assign: p Laboratories, North 2,979,534 4/1961 Petropouloset al ..260/6l9 Chicago, lll. OTHER PUBLICATIONS [22] Filed: 1970Solmssen Chem. Reviews Vol. 37 (1945), pages 566- [21] Appl. No.2 65,657567.

Lynch et al., J. Med. Chem., Vol. 11 (1968). pages Related U.S.Application Data 295.

[63] Continuation-impart of Ser. No. 604,126, Dec.

26, 1966, abandoned, which is a continuationry a ine -James A. Pattenin-part of Ser. No. 583,250, March 10, 1966, Attorney-Robert L. Niblackabandoned.

[57] ABSTRACT [52] U.S. Cl ..260/479 R, 260/612 R, 260/613 R.

260/619 F, 424/311, 424/341, 424/346 The present invention 18 directedto l-(4-substituted 511 Int. Cl. ....co7 69/16, C07c 43/22, co7 39/12benzylfindans and simple analogs thereof; y have [58] Field ofSearch.260/479 R, 612 R, 613 R, 619 F been found to inhibit themetabolic function of reproductive organs when administered to female,warm-blooded animals in very small doses.

7 Claims, No Drawings 1 l-(PARAOXYBENZYD-INDANE RELATIONSHIP TO OTHERAPPLICATIONS This application is a continuation-in-part of our previousapplication, Ser. No. 604,126, filed Dec. 26, 1966, which is acontinuation-in-part of Ser. No. 583,250 of Mar. 10, 1966, both nowabandoned.

DETAILED DESCRIPTION OF THE INVENTION The present invention is directedto l-(p-substituted benzyl)indan derivatives of the and wherein R is OH,methoxy or acetoxy, R is H or R and R" is H, methyl or acetyl.

The new compounds exhibit steroid-like activity; they inhibit themetabolic function of reproductive organs in female, warm-bloodedanimals and thus are useful to control the reproduction of mammals. Theymay be administered intramuscularly in dosages of from 0.1 to 2.5 mgJkg.as aqueous suspension or as vegetable oil solutions or they areadministered orally in dosages of from between 0.1 to 4 mgJltg.

The new compounds are prepared by condensing the ketone of formula N w nwherein R is methoxy and R is H or R with a p-substituted benzylGrignard reagent of the formula In a specific embodiment of the presentinvention, the reaction leading to the new products is carried out in anitrogen atmosphere and preferably, the abovenamed ketone is addedslowly to the solution, followed by refluxing for a period of between l5minutes and several hours. The reaction mixture is cooled and the liquidphase is poured into ice water to decompose the Grignard complex. Themagnesium hydroxide so formed may be solubilized by use of ammoniumsalts and/or hydrochloric acid to permit easier separation of thephases. The desired product is then isolated from the organic phase. Thebenzylidene compounds of formula 11 so obtained may be hydrogenatedcatalytically to the corresponding benzyl compounds of formula I, usingpalladium as the catalyst. The rnethoxy groups present in the A-ring maybe cleaved to produce the hydroxy derivatives. Alternately, the methoxygroup or groups can first be cleaved and the corrg hydroxy compounds canthen be hydrogenated to the corresponding saturated B-ring compound. Thehydroxy group or groups may be esterified by standard methods withacetyl chloride or acetic anhydride.

To illustrate the preparation of the new compounds reference is made tothe following examples which are not intended to limit the invention inany respect.

EXAMPLEI.

l-(p-Methoxybenzylidene)-5-methoxyindan A solution of 29.l g. of anisylchloride (b.p. 96.5-98 C. 5.8-5.9 mm.) in l 10 ml. ofdry ether is addedin a nitrogen atmosphere to a mixture of 200 ml. of dry ether, 17 g. ofmagnesium tumings and 17 g. of 40 mesh magnesium powder over a period of3 hours and 40 minutes. The mixture is stirred rapidly during theaddition.

A solution of 9.2 g. of S-methoxy-l-indanone in ml.ofdrybenmeneisaddedtothe above mixture over a period of 5 minutes. Anadditional ml. of benzene isaddedandthemixtureisstirredunderrefluxinanitrogen atmosphere for 3 hours. After cooling the mixture to roomtemperature, the liquid phase is decanted into a mixture of ice and 720ml. of 10 percent aqueous ammonium chloride. The organic layer isseparated, washed with water and dried over magnesium sulfate. Thesolvent is removed under reduced pressure to leave 26.4 g. of a residuewhich is crystallized from benzene to give 14 g. of white crystalsmelting at l34-8 C. (clear melt at C.) identified as title."

. E L 2 l-( p-I-lydroxybenzylidene )-5-l-lydroxyindan A mixture of l g.of l-(p-methoxybenzylidene)-5- methoxyindan and 3.23 g. of pyridinehydrochloride is heated at 20$-2l0 C. with stirring under nitrogen for50 minutes, cooled in an ice bath, and diluted with 25 ml. of water. Themixture is then made alkaline with a 5 percent aqueous sodium hydroxidesolution and extracted with ether. The alkaline aqueous phase isacidified with 5 percent aqueous hydrochloric acid and extracted withether. The ether extraction is washed with water, dried and the solventis evaporated leaving 0.69 g. ofl-(p-hydroxybenzylideneJ-S-hydroxyindan.

Crystallization of the crude material from ethyl acetate l-(p-Acetoxybenzylidene)--Acetoxyindan To a solution of 1.55 g. of thecompound of Example 2 dissolved in 21 ml. of pyridine is added dropwise5 ml. of acetic anhydride and the mixture is swirled for minutes at roomtemperature and allowed to stand overnight. The mixture is diluteddropwise with 6 ml. of water while swirling over a lS-minute period withslight cooling. Further dilution produces an oil which is extracted withether. The ether extract is washed in turn with 5 percent aqueoushydrochloric acid, water, 5 percent aqueous sodium carbonate and water.The organic phase is dried over magnesium sulfate and the solvent isremoved under reduced pressure to leave 2.0 g. of a colorless oil whichslowly crystallizes on standing. Crystallization from benzene/hexanegives 1.5g. of l- (p-acetoxybenzylidene)-5-acetoxyindan melting at l68C. (cloudy at l58-6l C.)

EXAMPLE 4 l-( p-Methoxybenzylidene)-S,6-Dimethoxyindan By repeating theprocedure of Example 1, using 5,6- dimethoxy-l-indanone and anisylGrignard as the starting material, l-( p-methoxybenzylidene)-5,6-dimethoxyindan melting at l58-60 C. after recrystallization fromacetone is obtained.

EXAMPLE 5 l-( p-Methoxybenzyl)-5,6Dimethoxyindan A solution of 3.5 g. ofthe compound of Example 4 in glycol monomethyl ether is hydrogenated at-40 psi. hydrogen pressure in the presence of 0.07 g. of palladiumdeposited on 1.33 g. of carbon. After hydrogen uptake ceases, thesolution is filtered under reduced pressure and the solvent is strippedunder reduced pressure leaving an oil which crystallizes upon standing.Recrystallization of this crude material from ethanol produces pure 1-(p-methoxybenzy1 )-5 ,6-dimethoxyindan melting at 74.S-76.5 C.

EXAMPLE 6 l-(p-Methoxybenzyl)-5-Methoxyindan This compound is obtainedby following the procedure of Example 5 with the compound of Example l.Recrystallization of the crude hydrogenation product from ethanolproduces the pure compound melting at 67.570.0 C.

EXAMPLE 7 l-( p-l-lydroxybenzyl )-5,6-Dihydroxyindan By following theprocedure of Example 2 with the compound of Example5,l-(p-hydroxybenzyl)-5,6- dihydroxyindan is obtained. However, due tothe instability of the compound of this compound in an alkaline medium,no sodium hydroxide is added to the reaction mixture and it is extracteddirectly with ether. The pure compound melts at l624 C. afterrecrystallization from ethanol/benzene/hexane.

t .i. n.

EXAMPLE 8 l-(p-HydroxybenzyD-S-Hydroxyindan By following the procedureof Example 2 with the compound of Example 6,1-(p-hydroxybenzylJ-S-hydroxymdan is obtained. The pure compound melts at l 59- 62bL C. afierrecrystallization fromether/benzene.

--..--.XAMR

l-(p-Acetoxybenzyl)-5-Acetoxyindan Repeating the process of Example 3with the compound described in Example 8, the desired indan melt- 1p-Acetoxybenzyl )-5 ,6-Diacetoxyin dan Acetylation according to Example3 is carried out with the compound of Example 7. Recrystallization ofthe crude material from benzene/hexane gives pure 1-(p-acetoxybenzyl)-5,6-diacetoxyindan melting at 1 30-2 C.

In all of the above tabulated examples, the infrared spectra andrnicroanalyses are in agreement with the assigned structures.

The new compounds may be administered intravenously, intramuscularly,subcutaneously, orally or in other suitable forms of applications towarm-blooded animals; in all these routes, suitable pharmaceuticalcarriers may be used to make pharmaceutical dosages forms such as pills,tablets, solutions, suspension and the like. The new compounds may beadministered alone or in admixtures with one another or together withother pharmacologicslly useful drugs.

We claim:

1. A compound of the formula wherein R is OH, methoxy or acetoxy, R' isH or R and R" is H, methyl or acetyl.

2. The benzylidene compound of claim 1 wherein R is OH and R and R" arehydrogen.

3. The benzylidene compound of claim I wherein R is acetoxy, R is H andR" is acetyl.

4. The benzyl compound of claim 1 wherein R is acetoxy, R is H and R" isacetyl.

5. The benzyl compound of claim 1 wherein R and R both are acetoxy andR" is acetyl.

6. The benzyl compound of claim 1 wherein R is OH and R and R" both areH.

7. The benzyl compound of claim 1 wherein R and R' both are OH and R" isH.

2. The benzylidene compound of claim 1 wherein R is OH and R and R''''are hydrogen.
 3. The benzylidene compound of claim 1 wherein R isacetoxy, R'' is H and R'''' is acetyl.
 4. The benzyl compound of claim 1wherein R is acetoxy, R'' is H and R'''' is acetyl.
 5. The benzylcompound of claim 1 wherein R and R'' both are acetoxy and R'''' isacetyl.
 6. The benzyl compound of claim 1 wherein R is OH and R'' andR'''' both are H.
 7. The benzyl compound of claim 1 wherein R and R''both are OH and R'''' is H.